Epidermal growth factor (EGF) is a 53 amino acid cytokine which is proteolytically cleaved from a large integral membrane protein precursor. EGF plays an important role in the growth control of mammalian cells. The amino acid and nucleotide sequences of human EGF (EGF) are, for example, disclosed in Hollenberg, “Epidermal Growth Factor-Urogastrone, A Polypeptide Acquiring Hormonal States”; eds., Academic Press, Inc., New York (1979), pp. 69-110; or Urdea et al., Proc. Natl. Acad. Sci. USA. 80, 7461 (1983). The amino acid sequence of EGF is also disclosed in U.S. Pat. No. 5,102,789 and copending U.S. patent application Ser. No. 10/820,640 both of which are incorporated herein by reference in their entirety.
Human Epidermal Receptors (HER), including epidermal growth factor receptors (EGFR), are well known example of receptor tyrosine kinases. Interaction of HERs with their cognate ligands, or with structurally related ligands, leads to dimerization and activation of the kinase domain. This initiates a signaling cascade, leading to cell division. Overexpression of the genes coding for HER family members has been implicated in a number of cancers including breast, ovarian, and head and neck cancer. Molecules that target EGFR (HER1) by inhibiting its kinase activity or by interfering with the binding of EGF to EGFR have been shown to inhibit cell proliferation and have been developed as anticancer therapeutics, for example, Iressa® (gefitinib), a tyrosine kinase inhibitor and Erbitux™ (cetuximab), an EGFR-specific monoclonal antibody. Additional molecules including monoclonal antibodies such as Herceptin target other individual members of the HER family. Recently, several monoclonal antibodies and small molecule kinase inhibitors (e.g. Panituzumab and Lapatnib) have entered development as examples of molecules that target multiple HER receptors. Although these therapeutics have been shown to be effective in some cases, there is still a need for novel therapies for HER-related cancers, particularly a therapeutic compound that interferes with the entire HER family.